Airway remodeling and emphysema accompany asthma, chronic obstructive pulmonary disease (COPD), BPD, and cystic fibrosis, contributing to high incidence of morbidity and mortality associated with these common disorders. Cellular processes, underlying the pathogenesis of these chronic lung diseases include abnormalities in epithelial cell differentiation, interstitial thickening, and inflammatory cell influx. The present grant application focuses attention to the primary role of the respiratory epithelium in processes influencing postnatal lung morphogenesis and remodeling. Preliminary data provided with the application demonstrate that transcriptional proteins of the forkhead family, Foxa1 and Foxa2, are expressed in epithelial cells of the lung during morphogenesis and postnatally. Lung specific, targeted deletion of Foxa2 perturbed alveolarization, caused airway remodeling, and goblet cell hyperplasia, inflammation, and airways hyperactivity. Thus, Foxa2 plays a critical and unexpected role in the formation and maintenance of the postnatal lung, regulating cell differentiation in both proximal and peripheral airways. The present grant will test the hypothesis that Foxa2 and Foxa1 play distinct and critical roles in the differentiation of respiratory epithelium that, in turn, influences lung structure and function, serving to maintain alveolar and airway homeostasis. This proposal will determine the effects of deletion and addition of Foxa2 and Foxa1, separately and in conjunction, on the formation, remodeling, and responses of the lung to inflammation in vivo. Mechanisms regulating Foxa2 and Foxa1 gene expression in the lung will be discerned in vitro and in vivo. Bioinformatics and genomic approaches will be used to define the molecular pathways regulating Foxa1 and Foxa2 expression and function. Effects of Foxa2 and Foxa1 on respiratory epithelial cell differentiation, function, and gene expression will be determined in transgenic models in which recombinant Foxa1 and Foxa2 are expressed. Transcriptional targets of Foxa2 and Foxa1 will be discerned using genomics/bioinformatics and RNA arrays. Mechanisms and pathways by which Fox family members regulate selected gene targets underlying epithelial cell differentiation and function will be discerned. The role of Foxa2 and Foxa1, as modifiers of the pathogenesis of lung disease and infection, will be assessed in oxygen and pathogen-induced lung injury.